Cytosolic phospholipase A 2 regulates lipid homeostasis under osmotic stress through PPARγ

• Published in: The FEBS journal 2024-02, Vol.291 (4), p.722-743
• Main Authors: Parra, Leandro Gastón, Erjavec, Luciana Cecilia, Casali, Cecilia Irene, Zerpa Velazquez, Andrea, Weber, Karen, Setton-Avruj, Clara Patricia, Fernández Tome, María Del Carmen
• Format: Article
• Language: English
• Subjects: Animals; Arachidonic Acid - metabolism; Dogs; Glycerophospholipids; Homeostasis; Indomethacin; Osmotic Pressure; Phospholipases A2; PPAR gamma - genetics; Prostaglandins; Rosiglitazone; Triglycerides
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16998

Physiologically, renal medullary cells are surrounded by a hyperosmolar interstitium. However, different pathological situations can induce abrupt changes in environmental osmolality, causing cell stress. Therefore, renal cells must adapt to survive in this new condition. We previously demonstrated that, among the mechanisms involved in osmoprotection, renal cells upregulate triglyceride biosynthesis (which helps preserve glycerophospholipid synthesis and membrane homeostasis) and cyclooxygenase-2 (which generates prostaglandins from arachidonic acid) to maintain lipid metabolism in renal tissue. Herein, we evaluated whether hyperosmolality modulates phospholipase A (PLA ) activity, leading to arachidonic acid release from membrane glycerophospholipid, and investigated its possible role in hyperosmolality-induced triglyceride synthesis and accumulation. We found that hyperosmolality induced PLA expression and activity in Madin-Darby canine kidney cells. Cytosolic PLA (cPLA2) inhibition, but not secreted or calcium-independent PLA (sPLA or iPLA , respectively), prevented triglyceride synthesis and reduced cell survival. Inhibition of prostaglandin synthesis with indomethacin not only failed to prevent hyperosmolality-induced triglyceride synthesis but also exacerbated it. Similar results were observed with the peroxisomal proliferator activated receptor gamma (PPARγ) agonist rosiglitazone. Furthermore, hyperosmolality increased free intracellular arachidonic acid levels, which were even higher when prostaglandin synthesis was inhibited by indomethacin. Blocking PPARγ with GW-9662 prevented the effects of both indomethacin and rosiglitazone on triglyceride synthesis and even reduced hyperosmolality-induced triglyceride synthesis, suggesting that arachidonic acid may stimulate triglyceride synthesis through PPARγ activation. These results highlight the role of cPLA in osmoprotection, since it is essential to provide arachidonic acid, which is involved in PPARγ-regulated triglyceride synthesis, thus guaranteeing cell survival.